There is now substantive evidence that hypertension and cardiovascular disease may result from insults that are inflicted on the developing fetus. Prenatal glucocorticoids are frequently administered to pregnant women to accelerate pulmonary lung maturation. In preliminary data we have found that administration of dexamethasone to pregnant rats at specific times during fetal development results in hypertension when the animals were studied as adults. While previous studies have hypothesized and provided indirect evidence that there is an alteration in sodium transport, this has not been critically or directly examined. The overall goal of this proposal is to determine how prenatal insults program hypertension in later life. We aim to determine the mechanism of the altered sodium transport by prenatal programming. In preliminary data we show that prenatal administration of dexamethasone to pregnant rats results in an increase in proximal tubule sodium transport. We plan to examine the nephron segments involved and the mechanism for this increase in tubule transport using in vitro microperfusion and in vivo micropuncture. We aim to determine if the increased proximal tubule sodium transport by prenatal dexamethasone is via dysregulation of the proximal tubule renin- angiotensin system. We present preliminary data showing that there is an alteration in the intrarenal renin-angiotensin system by prenatal programming and will examine directly if the endogenous proximal tubule renin-angiotensin system mediates the altered sodium transport by prenatal programming in rats. In preliminary data we show that renal denervation results in a normalization of the blood pressure in rats exposed to prenatal dexamethasone, while denervation did not affect the blood pressure in control animals. We aim to examine the mechanism for the amelioration in blood pressure by renal denervation and if this is linked to the intrarenal renin-angiotensin system. Finally, there are two widely studied models for prenatal programming of hypertension; dietary protein deprivation and maternal glucocorticoid exposure. These two models may be connected since maternal dietary protein deprivation in pregnant rats leads to lower placental 11 ?-hydroxysteroid dehydrogenase activity and potentially greater fetal exposure to maternal glucocorticoids. We will dissociate maternal dietary protein deprivation from fetal exposure to maternal glucocorticoids to determine if maternal glucocorticoid exposure is the cause for hypertension, a reduction in nephron number and altered tubular transport with maternal dietary protein deprivation. PUBLIC HEALTH RELEVANCE: There is now substantive evidence that hypertension and cardiovascular disease may result from insults that are inflicted on the developing fetus. Prenatal glucocorticoids are frequently administered to pregnant women to accelerate pulmonary lung maturation. We show that prenatal dexamethasone can result in the development of hypertension when administered during specific times during fetal development. This proposal aims to determine how prenatal dexamethasone causes hypertension.